La radioimmunotherapie (RIT) est une strategie theranostique associant la specificite de reconnaissance d’anticorps monoclonaux (AcMs) (ou de formes derivees) vis-a-vis des antigenes tumoraux et les proprietes des radionucleides (imagerie/therapie). L’efficacite de la RIT est cependant limitee sur les tumeurs solides a cause de la lente diffusion des AcMs et de leur longue demi-vie plasmatique. Les approches de radioimmunotherapie preciblee (PRIT), qui dissocient l’injection des AcMs de celle des radioligands constituent des alternatives pertinentes envisagees pour diminuer l’hematotoxicite et ameliorer l’efficacite therapeutique de la RIT classique. Nous avons ainsi travaille sur une strategie de PRIT utilisant la chimie bioorthogonale par interaction entre un trans-cyclooctene (TCO) et une tetrazine (TZ), a la fois pour l’imagerie et pour la therapie de la carcinose peritoneale (CP) d’origine colorectale (modele A431-CEA-Luc/ AcM 35A7). Dans un premier temps nous avons evalue a la fois in vitro et in vivo dans le modele de CP ainsi que dans un modele sous-cutane de cancer colorectal (modele HT29/ AcM Ts29.2) l’effet des modifications apportees aux AcMs. Nous avons ainsi montre que les modifications d’AcMs influencent l’interaction entre les TCO et la TZ, sans pour autant alterer leur immunoreactivite. L’ajout d’espaceurs PEGyles (polyethylene glycol) entre les AcMs et les TCO induit une diminution significative de l’interaction TCO/TZ. De plus, nous avons montre que les TCO sont sujets a l’isomerisation en cis-cyclooctenes, inactifs vis-a-vis de la TZ, et que la PEGylation aggrave ce phenomene. Ces etudes ont ainsi montre a la fois que les AcMs-TCO ne contenant pas d’espaceur PEGyle etaient les plus favorables pour le preciblage mais egalement, qu’il etait primordial de controler le taux d’isomerisation des TCO avant greffage aux AcMs pour ne pas alterer l’interaction vis-a-vis des TZ. Dans un second temps nous avons effectue avec succes la preuve de concept de l’imagerie SPECT de la CP par preciblage entre l’AcM 35A7-TCO et la TZ-PEG4-DOTA-177Lu (i.e. TZ-1). Un ciblage specifique des tumeurs peritoneales a ainsi ete obtenu, avec un tres bon contraste. L’etude de PRIT effectuee avec cette meme sonde TZ-1 a cependant echoue a mettre en evidence une amelioration des medianes de survie ou un ralentissement de la croissance tumorale, nous amenant ainsi a reconsiderer la structure de la TZ-1. Trois autres TZ (i.e. TZ-2-4) ont donc ete evaluees par la suite, en biodistribution, afin de determiner la meilleure pour la PRIT de la CP. Ainsi, la TZ-3, qui comporte un espaceur PEGyle plus long que la TZ-1, s’est averee etre la plus favorable dans ce type de strategie et sera prochainement utilisee pour une nouvelle etude de therapie. En conclusion, ces travaux de these ont permis de demontrer la faisabilite du concept de preciblage par chimie bioorthogonale utilisant l’interaction TCO/TZ pour l’imagerie de tumeurs disseminees dans la cavite peritoneale. Cette strategie reste neanmoins compliquee a mettre en place du fait de l’instabilite des TCO et des problemes de reactivite de certaines sondes TZ et necessite encore de nombreuses optimisations avant de pouvoir envisager une application therapeutique.

https://tel.archives-ouvertes.fr/tel-02275818/document

Radioimmunothérapie préciblée de la carcinose péritonéale par chimie bioorthogonale

Purpose Psammocarcinoma (PK) is a rare disease of unknown origin. We aimed to report the characteristics, management and survival of patients operated on for PK within the French Network for Rare Peritoneal Malignancies (RENAPE) expert centers. Patients and methods All consecutive cases of PK operated within all 26 RENAPE centers between 1997 and 2018 were retrospectively analyzed. Results Twenty-five patients were identified. The median age was 53 years [range 17–78]. None of the patients had extra peritoneal metastases at diagnosis. A median of 6 cycles of carboplatin-based systemic chemotherapy was delivered in 52% preoperatively (n = 13) and 56% postoperatively (n = 14); associated with placlitaxel for 12 patients. All patients were operated on. The median PCI was 23 [0–33]. Eighty-four percent had a complete cytoreductive surgery through digestive (n = 7), spleen (n = 3), pancreas (n = 1) resections and/or multiple peritonectomies (n = 11). Five patients (20%) had intraperitoneal chemotherapy. Morbidity (Dindo-Clavien ≥3) was 12%. No postoperative death occurred. After a median follow-up of 42 months (range [2–194]), the median overall (OS) and progression-free (DFS) survival times were respectively 128 months and 31 months. Eighteen patients recurred (72%), mainly in the peritoneum (n = 16). Four of them (22%) were reoperated. The 5 and 10-year DFS rates were both 20.3%. The 5 and 10-year OS rates were 62% and 51.7%, respectively. A complete cytoreductive surgery was associated with a better OS and DFS in a univariate analysis. Conclusion Complete cytoreductive surgery is the cornerstone of the PK's management as a primary treatment. Recurrence remains common and new adjuvant strategies seem needed.

Ovarian and peritoneal psammocarcinoma: Results of a multicenter study on 25 patients.

Psammocarcinoma is an uncommon subtype of low-grade serous carcinoma. It is characterized by the presence of extensive psammoma bodies and can have either an ovarian or peritoneal origin. To our knowledge fewer than 30 cases of primary peritoneal psammocarcinoma (PPP) have been reported in the English literature. We report a rare case of  PPP in a 74-year-old female, discovered fortuitously within a laparotomy for gallbladder lithiasis. At laparotomy, multiple nodular implants involving the omentum, the peritoneum and a magma of intestinal loops in the right iliac fossa were noted. A biopsy from nodules was performed. Gross examination showed multiple nodules of different sizes in the fat tissue. Pathologic examination showed massive psammoma bodies representing more than 75% of the tumor. The final diagnosis was psammocarcinoma. Our patient was referred to the gynecologic department for further investigation and to ascertain whether the tumor arose from the ovaries or peritoneum. Hysterectomy, bilateral adnexectomy and omentectomy were performed. Macroscopic examination showed that both ovaries were intact having a normal size. No invasion of ovarian stroma was shown in microscopic examination. The patient died of SARS-CoV-2 (COVID-19) six days after the surgery. PPP is a rare type of  low-grade serous carcinoma. The behavior of this tumor is unclear, and the treatment is not standardized because of its rarity and lack of long-term follow-up. More cases need to be studied for better understanding and improvement of the management protocols.

https://f1000research.com/articles/11-696/v1/pdf

Case Report: Fortuitous discovery of primary peritoneal psammocarcinoma

Psammocarcinoma is a rare low-grade serous carcinoma arising either from ovary or peritoneum and is characterized by extensive psammomatous calcifications and invasion of surrounding structures. Prognostically, psammocarcinoma resembles borderline serous tumor and has a much more favorable outcome than the common serous carcinoma of ovary and peritoneum.

Akash Jogi

Papers

Primary peritoneal psammocarcinoma.

Solitary Fibrous Tumor of Head & Neck Region: Problems in Diagnosis Due to “Borderline” Features